Various central nervous system disorders such as depression, anxiety, etc. appear to involve the disturbance of the neurotransmitters noradrenaline (NA) and/or 5-hydroxytryptamine(5-HT), the latter also known as serotonin. The drugs most frequently used in the treatment of depression are believed to act by improving the neurotransmission of either or both of these physiological agonists. It appears that the enhancement of 5-HT neurotransmission primarily affects the depressed mood and anxiety, whereas the enhancement of noradrenaline neurotransmission affects the retardation symptoms occurring in depressed patients.
Serotonin, or 5-HT, activity is thought to be involved in many different types of psychiatric disorders. For instance it is thought that an increase in 5-HT activity is associated with anxiety, while a decrease in 5-HT release has been associated with depression. Serotonin has in addition been implicated in such diverse conditions as eating disorders, gastrointestinal disorders, cardiovascular regulation and sexual behavior.
The compound of formula I below in base form has an extremely low solubility in water and a slow release rate which rate is pH dependent, i.e. the rate is different in the stomach and the intestines. From a pharmaceutical formulation point of view it is very difficult to dissolve the base rapidly enough and maintain the same dissolved in the gastric juice until a sufficient amount of substance has been absorbed.
The 5-HT Receptors
The various effects of 5-HT may be related to the fact that serotoninergic neurons stimulate the secretion of several hormones, e.g. cortisol, prolactin, B-endorphin, vasopressin and others. The secretion of each of these other hormones appears to be regulated on a specific basis by several different 5-HT (serotonin) receptor subtypes. With the aid of molecular biology techniques, to date these receptors have been classified as 5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3, 5-HT.sub.4, 5-HT.sub.5, 5-HT.sub.6 and 5-HT.sub.7 with the .sup.5 -HT.sub.1 receptor further divided into the 5-HT.sub.1A, 5-HT.sub.1B, 5-HT.sub.1D, 5-HT.sub.1E and 5-HT.sub.1F subtypes. Each receptor subtype is involved in a different serotonin function and has different properties.
Regulation of the 5-HT transmission
The release of 5-HT at the nerve terminals is feedback-regulated by two different subtypes of 5-HT receptors. Inhibitory 5-HT.sub.1A autoreceptors are located on the cell bodies in the raphe nuclei which upon stimulation by 5-HT decrease the impulse propagation in the 5-HT neurons and thereby reducing the 5-HT release at the nerve terminals. Another subtype of inhibitory 5-HT receptors is located on the 5-HT nerve terminals, the h5-HT.sub.1B receptors (in rodents the r5-HT.sub.1B receptors) which regulate the synaptic concentration of 5-HT by controlling the amount of 5-HT that is released. An antagonist of these terminal autoreceptors thus increases the amount of 5-HT released by nerve impulses as has been shown in both in vitro and in vivo experiments.
The use of an antagonist of the terminal h5-HT.sub.1B autoreceptor will accordingly increase the synaptic 5-HT concentration and enhance the transmission in the 5-HT system. It would thus produce an antidepressant effect making it useful as a medication for depression.
Other localizations of h5-HT.sub.1B receptor subtype also exist. A large part of these postsynaptic receptors appear to be located on nerve terminals of other neuronal systems (so called heteroreceptors). Since the h5-HT.sub.1B receptor mediates inhibitory responses an antagonist of this receptor subtype might also increase the release of other neurotransmitters than 5-HT.
Compounds having h5-HT.sub.1B activity may according to well known and recognised pharmacological tests be divided into full agonists, partial agonists and antagonists.